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SENSORINEURAL HEARING LOSS AND NANOOTOLOGY

    - Will the Small and the Little be Louder?

Dr 'Biodun Olusesi

Introduction

Problem Formulation and Analysis

Nanotechnology - Concepts

Nanootology

Early Promises of Nanootology

References

Other Scientific Papers

Introduction

Management of deafness due to cochlear or retrocochlear lesions has always perplexed clinicians over the ages. While it was widely believed that little beyond rehabilitation could be done for most persons with such deafness, the cornerstone of possible treatment rests upon an exact diagnosis where possible. [1] The diagnostic parameters used are often clinical and audiological, with radiological, laboratory and genetic screening just assuming wide acceptance. These newer diagnostic modalities are commonly used to delineate syndromic from non-syndromic sensorineural hearing loss. Routine laboratory evaluation carried out on those with suspected sensorineural hearing loss was recently shown to give low diagnostic yield. [2] Even with the radiologic studies, the most common isolated CT finding in unexplained sensorineural hearing loss was large vestibular aqueducts, and beside helping to counsel against head trauma, this finding yields little information to assist in restoring hearing. Common etiological factors for cochlear deafness are Aging, Noise, ototoxicity, labyrinthitis, genetic and endolymphatic hydrops, while retrocochlear deafness commonly results from acoustic tumour, head trauma, and central auditory nervous system disorders [3]. Recent World Health Organization’s publication grouped hereditary and Presbycusis as major causes of high frequency hearing loss; Excessive noise, ototoxicity and viral labyrinthitis as causes of moderate frequency hearing loss, while cerebrovascular disease, head trauma, and endolymphatic hydrops were observed to cause low frequency hearing loss. [4]. Some of the studies on deafness from developing countries have mostly identified bacterial (Meningitis, Chronically discharging ear) and Viral (Measles, Mumps) labyrinthitis as common etiologic causes of deafness among the deaf populations [5, 6, 7, 8]. Such studies however often reported a significant proportion of the study sample as having idiopathic hearing loss, possible partly due to severely limited facilities available for exact diagnosis. Other workers reported a high proportion of deafness due to genetic causes. [9, 10].

Current management options for sensorineural hearing loss include

  1. Medications – Steroids, cytotoxic drugs – in cases of autoimmune etiology
  2. Wearable Amplifications (Hearing aids)
  3. Implantable Amplifications (Hearing aids, cochlea implants, auditory brainstem implants)
  4. Speech and auditory trainings, as well as assistive listening devices.

  Among the factors that made this type of deafness to be regarded as untreatable over the ages are (a) the relative inaccessibility of the human cochlea; and (b) the poorly understood knowledge of the genetic regulation of hair cell functions, couple with the long-held assumption that central nervous system cells are permanent cells incapable of regeneration after death.

With increasing knowledge of the comparative anatomy and physiology of hearing in avian and lower mammals, and with burgeoning interest in molecular basis of hereditary and acquired deafness and vestibular disorders following the completion of the human genome project, there is a ray of hope that majority of sensorineural hearing loss may soon become treatable. This hope is further reinforced by the availability of powerful computer tools to precisely simulate the cochlear function and give better understanding of the hearing process.

NANOOTOLOGY

  Nanootology is the application of nanomedicine to otological diseases management. The practitioner or nanootologist will employ the use of nanodevices for diagnostic and therapeutic purposes, assisted by the nanocomputer. It is envisaged that, working at such sub-microscopic level, the nanootologist will have significant advantage over the present age otologist by the capacity to operate at the cellular level. At present, the options available to the otologist confronted with individuals with hearing loss include (a) wait and see; (b) prescription of wearable amplification; (c) prescription of implantable amplification; (d) Drug medication; and (e) prescription of auditory and speech training as well as use of assistive listening devices.

A recent world health organization’s bulletin indicated that less than 1 in 40 of hearing aids needed in developing countries get there [19]. Also very few centers in developing countries have facilities for cochlear implants, and where such exist, the cost of implantation is far beyond the reach of majority of suitable candidates for such implants. Looking forward to the promises of Nanotechnology then, and extrapolating such to the expected solutions to the treatment of sensorineural hearing loss provides an expectant welcome relieve. The following breakthroughs in Nanotechnology provide a reason for such hope:

  1. Microsized microscope. Developed by Luke P.Lee at the UC Berkely, this microscope equipped with microlens that measures only 300 microns in diameter can provide doctors with a view of DNA of individual cells inside a patient as drugs are delivered.[24]
  2. DNA control. Using nanomaterials, J Jacobson and S Zhanag of MIT Research Media laboratory have demonstrated a gadget capable of turning genes on and off [25].
  3. A dendrimers capable of carrying receptor binding proteins, florescent materials, drug molecule, metals, and signal for cell death has been developed by James Baker of the University of Michigan [26].
  4. Yoshihija Suzuki of Kyoto University has demonstrated a device that releases antibodies only in the presence of an infection. This demonstration thus brings science closer to the possibility of smart drugs and programmable immune mechanism [27].
  5. A new cheap DNA detection method has been described that utilize  electrodes and nanoprobes for reading DNA in samples have been demonstrated. This promises to replace the gene chips based on PCR for DNA detection and expensive confocal microscopy for DNA reading [28].
  6. Carbon nanotubes capable of detecting a single molecule of glucose, as well as nanowires that can detect single virus have been recently demonstrated.[29,30].

  The prospects of these to nanootology is that the otological surgeon, operating at the nanoscale will be better equipped to

    1. deliver smart drugs to the inner ear;
    2. manipulate the hair cells to effect repair or even replacement;
    3. diagnose and test the effects of varying injurious agents – bacteria, viruses, toxins, radiation, etc – on the hair cells in vivo;
    4. tackle the issue of neurological damage that is central to retro-cochlear deafness; and
    5. detect and repair genetic damages to the hair cells without resorting to the hazardous and less effective viral vectors.

Nanotechnology - Concepts

Nanotechnology is the science concerned with building, visualizing and manipulation of things at the submicroscopic (nanoscale) level. Monitoring intracellular events at the biological scale has always been limited the resolution power of the microscope available to different age. Active intervention of the events at that scale has always been regarded as pie-in-the-sky fantasy of scientific fiction writers. The first challenge to scientist to aim for that scale came from the late Physics Nobel laureate – Richard P.Feyman – in a 1959 lecture titled ‘There is Plenty of Room at the Bottom’ [18]. A renewed interest in Feyman’s challenge developed when Richard Smalley, who shared the 1996 Nobel prize in chemistry discovered the carbon nanotube in soot from a carbon arc lamp. The soccer-shaped molecule made up of 60 carbon atoms which Smalley discovered was named fullerene.

Carbon nanotubes, made up of a sheet of graphite are strong, flexible and extremely sensitive to chemical (exposure to chemicals result in change in their electrical conductance). These properties implied that they could be used as ultra sensitive chemical sensors, or as semiconductors in integrated circuits, or be built into nanowires to control electrical currents, emit light, heat or cool a device, or store information, or even used as microscopic systems to read individual strands of DNA. This convergence of information technology, biotechnology and Nanotechnology promptly gained global attention as ‘supersmall solutions to some very bug problems’.

The discovery of vast potentials of carbon nanotubes prompted re-visiting of the tree-shaped synthetic molecule called Dendrimers, invented by Donald Tomalia two decades earlier.  Dendrimers are formed nanometer by nanometer; they have surface made to form dense field of molecular groups that serve as hooks, and they can carry internal molecular baggage. These properties make dendrimers ideal excellent transporters for sneaking DNA into cells, and a whole new view of genetic transfer suddenly came into view. Another important invention of Nanotechnology to enable monitoring of intracellular events is the quantum dot nanocrystals

Problem Formulation And Analysis

  1. The human cochlea measures about 35 mm in length. The functional unit of the auditory cochlea is the organ of Corti. Table1 illustrates the current knowledge on the relative dimensions of the structures that made up the organ of Corti.

This knowledge is required if we are to be able to manipulate the cochlear hair cells at the molecular level. Most of our current knowledge of hair cells function emanated from animal studies, from labyrinthine tissue obtained from patients during surgery for acoustic neuromas, and from cadaveric temporal bone preparations. There is presently no way to study hair cells in vivo, and no adequate diagnostic procedures to evaluate the functions of the inner hair cells or the afferent synapse [11].

  1. Studies have shown that avians have high hair cells turnover [12]. Similar but limited long term recovery has also been observed in mammals following gentamycin-induced ototoxicity [13]. Understanding the genes that play roles in turning on and off such hair cells might provide insight into how human hair cells could be made to regenerate. At present, attempts at genetic therapy of inner ear diseases mostly rely on using the virus as a vector to transfect genes into inner ear, and this is highly inefficient with occasional mortality reported [14].
  2. Studies have demonstrated that cochlear development occurs independent of auditory nerve development [15]. This has resulted in the new, though still controversial concept of auditory neuropathy, and has set the stage for independent manipulation of cochlear and retrocochlear lesions at the molecular level.
  3. The molecular process that occurs within the cochlea is being increasingly understood. The base to apex gradient of cell death seen in hearing loss following ototoxicity, noise trauma and Presbycusis is now believed to be due to differential distribution of cellular antioxidants (glutathione) and enzymes (superoxide dismutase) that protect the cells against free oxygen radicals generated by such etiologies [16]. The molecular events during mechano-sensory transduction is also being increasingly studied. The genes that code for the gap junction proteins (connexins) through which potassium ions pass during mechano-sensory transduction have been isolated, further setting the stage for manipulation of molecular events at the level of individual hair cells
  4. Certain genes are known to be expressed during cochlear development, and these have been cloned in man and lower mammals [17]. Further understanding of the roles played by such genes could assist our understanding and management of hearing loss of genetic etiology

  Fallout of the developments and progress in auditory research stated above is our increasing understanding of the phenomena of plasticity, hair cell regeneration and gene therapy. Since the basis for development, differentiation, regeneration and plasticity of tissue is differential gene expression, if we could (a) identify differentially expressed genes during cochlear development, (b) identify which genes are turned on by avian cochlear and vestibular hair cells to effect regeneration, and (c) identify which genes are down regulated as a result of several insults to the cochlea (Labyrinthitis, acoustic trauma, ototoxicity, etc), then we could be able to effect repair of damage hair cells by turning such regulatory genes on. We could even replace damaged hair cells completely rather than repair them. These are the promises of Nanootology.

Early Promises of Nanootology

Robert Freitas Jnr,  the author of Nanomedicine has already highlighted the broad future applications of Nanotechnology to medicine as a whole [20]. The early applications to otology conceived include

  1. Drug delivery to the inner ear
  2. Diagnoses and treatment of vestibular schwannomas
  3. Diagnoses and treatment of autoimmune inner ear disease
  4. Diagnosis and treatment of hearing loss due to genetic etiology

However, the long-term applications conceived is very broad as Nanootology hold promises of revolutionizing otology the same way the introduction of endoscopes has revolutionized the practice of rhinology

  1.Drug delivery to the inner ear: Studies have shown that at the molecular level, cellular damage due to noise and ototoxicity occurs secondary to a rise in the level of free oxygen radicals within the hair cells, and that hair cells could be protected by antioxidant and enzymes [16]. The nanootologist, using programmable molecular robots (nanobots) which could be injected into the forearm vein and guided into the labyrinthine artery via the vertebro-basilar arterial system, will be able to scan, diagnose, and deliver measured dose of drugs and chemicals to the hair cells as required. This may become the standard prophylactic treatment for acoustic trauma and ototoxicity, and has the added advantage of ease of administration and monitoring. Treatment could be administered over a network or even over the Internet. Also the present technique of intra-tympanic administration of gentamycin for incurable vertigo (chemical labyrinthectomy) is crude and destructive to the cochlear hair cells. Nanootology will make possible selective delivery of drugs to the vestibular hair cells if desired, with no effect on hair cells of the cochlea. The task to accomplish before this is made possible is to make the nanobot (a) resist filtration at the pulmonary microcirculation; (b) resist ingestion by macrophages and lymphocytes; (c) be mechanically coupled to blood and powered either by macronutrients in the blood, or by extrinsic power source; and (d) be mechanically coupled to the cell membrane of the cochlear microcirculation to facilitate diffusion out of these into the interstitial space within the cochlea.

  2. Diagnosis and treatment of vestibular schwannomas: At present, the diagnosis of vestibular schwannomas (VS) rely on the clinical history of deep otalgia, sensory deafness, tinnitus, facial paresis and or vertigo; audiological demonstration of delayed waves I to V inter-peak latency on ABR, and radiological demonstration of soft tissue mass within the internal auditory meatus (IAM ) or the cerebello-pontine angle (CPA) on magnetic resonance imaging (MRI). A proportion of VS have neurofibromatosis type 2 (NF-2), and such patients have other associated brain and spinal tumours, as well as ocular signs. Majority (over 90%) of NF-2 carriers however develop bilateral VS, and inheritance being autosomal dominant, such persons have 50% chances of transmitting the tumour to their offspring. Present management options include observation (for very small tumours), microsurgery, and radiosurgery [21]. Microsurgery, even in the hands of best surgeons often make facial and hearing preservations impossible, while radiosurgery has a higher recurrence and complication rate. Studies by Pelton et al have shown that both schwann cells and schwannoma cells express identical antigenic markers on their surface but schwanomas cell's stress fibres are inhibited by c3 transferase, tyrophoston A25, and RhoA [22]. The nanootologist could tag a nanobot or dendrimers with specific markers to seek out and unload antitumour agents only where schwanomas are present. The multifocus nature of the schwannomas seen in  NF-2 patients make this future treatment highly desirable over current treatment options.

  3. Treatment of Autoimmune Inner Ear Diseases (AIED)

Autoimmune inner ear disease (AIED), a syndrome of progressive sensorineural hearing loss and or vertigo believed to be caused by antibodies directed at the inner ear hair cells, is presently still largely a diagnosis of exclusion. Though it constitutes about 1% of hearing losses, this entity represents a treatable type of sensorineural hearing loss. At present there is no commercially available specific test for autoimmunity to the inner ear that is proven to be useful [23]. Diagnosis is often delayed, unless it is associated with other autoimmune conditions. Treatment of this condition is also controversial and rapidly changing with the use of immunosuppressive drugs (steroids, cytotoxics), and anti-TNF drugs as present options, and cochlear implants for those with bilateral acquired deafness. Over 65% of the sufferers are middle-aged females, in whom the prolong use of these agents carry added risks. Studies have shown that the labyrinth contains few resident leucocytes, and with compromised immunoregulation, the inner ear inflammation is mediated by cells that enter following the activation of the spiral modiolar vein [24]. It is believed that local therapy may be effective in treating this condition if it were to target leucocyte infiltration into the labyrinth.

With nanootology, surgeons could precisely diagnose the presence of autoimmunity to inner ear cells, as well as deliver measured and precise dose of drug or chemicals, either to neutralize the effects of the immunogenic cells in the inner ear, or to competitively block the receptor sites of such cells or chemicals. Repair and or replacement of affected hair cells is an added possibility with Nanootology.

References

  1.    B. Hill Britton: Radiologic evaluation of Sensorineural Hearing Loss. Otolaryngologic Clinics of North America Feb. 1978 Vol. 11, No.1: 3-6.

  2. Derek D. Mafong, Edward J. Shin, Anil K. Lalwani: Use of Laboratory Evaluation and Radiologic Imaging in the Diagnostic Evaluation of Children with Sensorineural Hearing Loss. Laryngoscope 2002; 112:1-
  3. John M. Page: Audiology – A Problem Oriented Approach. Otolaryngologic Clinics of North America – Vol. 11, No.3, October 1978
  4. Andrew Smith: In Prevention of deafness and blindness. World Health Organization. Available On Line: www.who.int/pbd/pdh/sshow/PDHforWEB2/sld022.htm
  5. Viljoean, D. L, Dent, G.M, Sibanda, A.G: Childhood deafness from Zimbabwe. South Africa Medical Journal, 73(5):286-288
  6. .Ijaduola G.T.A: The Problems of the Profoundly Deaf Nigerian Child. Postgraduate Doctor – Africa; June 1982:180-184
  7. MacPerson B, Holborow C.A: A study of deafness in West Africa – The Gambian Hearing Health Project. Int. J. Pediatr. Otorhinolaryngol. 1985 Nov, 10(2):115-35
  8. Holborrow C, Martinson F, Anger N: A Study of Deafness in West Africa. Int. J. Pediatr. Otorhinolaryngol. 1982 Jun; 4(2):107-32
  9. Sellars S.L, Beighton P: Aetiology of Partial Deafness In Childhood. S Afr. Med. J. 1978 Nov.11; 54(20):811-3
  10. Beighton P, Sellars S.L, Goldblatt J, Viljoen D.L, Beighton G: Childhood Deafness In The Indina Population Of Natal. S. Afr. Med. J. 1987 Aug.1; 72(3):209-11
  11.  Starr A, McPherson D, Patterson J, Luxford W, Shannon R, Sininger Y, Tonokawa L, & Waring M (1991). Absence of both auditory evoked potentials and auditory percepts dependent on time cues. Brain, 114, 1157-1180.
  12. DianneDurham, Debra L. Park, Douglas A. Girod: Central Nervous System Plasticity during Hair cell Loss and Regeneration. Hearing Research, volume 147, Issues 1-2, September 2000: 145-159.
  13. Walsh R.M, Hackney C.M & Furness D.N (2000): Regeneration of the mammalian vestibular sensory epithelium following gentamycin-induced damage. J. Otolaryngol. 2000 Dec; 29(6):351-60
  14. Boyce N: In memoriam – tougher rules could be the legacy of gene therapy’s first death. New Sci. 1999 Dec.18;164(2217):9
  15. Kral A, Hartman R, Tillein J, Heid S, Kleinke R: Hearing after congenital deafness – central auditory plasticity and sensory deprivation. Cereb. Cortex 2002 Aug; 12(8):797-807
  16. Mao Li Duan, Mats Ulfendahl, Goran Lamell, Allen S. Counter, Ilmai Pyykko, Eric Borg & Ulf Rosenhall: Protection and treatment of sensorineural hearing disorders caused by exogenous factors – experimental findings and potential clinical applications. Hear. Res. July 2002; 169(1-2):169-178
  17. Ralph H Hole, Tracy J. Bussoli & Karen P. Steel: Table of gene expression in developing ear. Available on Line. http://www.ihr.mrc.ac.uk/hereditary/genetable/search.shtml  (Assessed 03/11/2002)
  18. Richard P.Feynman: There is plenty of room at the bottom (1959 Lecture). Available On Line http://www.zyvex.com/nanotech/feynman.html  (Assessed 03/11/2002)
  19. Andrew Smith: In Prevention of deafness and Hearing impairment in developing countries. World Health Organization. Available On Line http://www.who.int/pbd/pdh/sshow/PDHforWEB2/sld022.htm (Assessed 03/11/2002)
  20. Robert A. Freitas Jr: The Future of nanofabrication and molecular scale-device in nanomedicine. Studies in Health Technology and Informatics 2002; 80:45-59. Available On Line. http://www.zyvex.com/Research/Publications/FutureNanofabNMed.html  (Assessed 06/11/2002)
  21. Nader R, Al-Abdulhadi K, Leblanc R, Zeitouni A: Acoustic Neuroma – Outcome study. J Otolaryngol 2002 Aug;31(4):207-10
  22. Pelson P.D, Shena L.S, Rizvi T.A, Marchioni M.A, Wood P, Friedman R.A, Rabner N: Ruffling membrane, Stress fibre, Cell spreading and Proliferation abnormalities in human schwanoma cells. Oncogene 1998. Oct 29; 17(17):2195-209.
  23. Timothy C.Hain: Autoimmune Inner Ear Disease. In American Hearing Research Foundation Website. Available On Linehttp://american-hearing.org/name/autoimmune.html (Assessed 03/11/2002)
  24. Ryan A.F, Hams J.P, Keithley E.M: Immune mediated Hearing Loss. Acta Otolaryngol Suppl 2002; (548):38-43
  25.  Jay Wrolstad: Mini-Microscope Looks inside Living Cells. Sci. Tech. Newsfactor. March 18, 2002. Available On Line. http://sci.newsfactor.com/perl/story/16823.html#story-stat  Accessed 5/11/2002
  26. Kimberly Hamad-Schifferly, John J.Schwatz, Aaron T.Santos, Shuguang Zhang & Joseph M.Jacobson: Remote electronic control of DNA hybridization through inductive coupling to an attached metal nanocrystal antenna. Laboratory of Molecular Self-assembly – Recent Publications. Available On Line. http://web.mit.edu/lms/www/02remote.shtml
  27. Eric J Lerner: “Nano is now at Michigan – and James Baker is leading the Way”. Medicine at Michigan Vol. 2 Number 2, Summer 2000. Available On Line http://medicineatmichigan.org/magazine/2000/summer/nanonman/default.asp
  28. Y. Suzuki, M. Tanihara, Y.Nishmura, K. Suzuki, Y.Kakimara, Y. Shimizio: A new drug delivery system with controlled release of antibiotic only in the presence of Infection. J. Biomed Mater. Res. Oct. 1998; 42:112-116
  29. So-Jung Park, T.Andrew Taton, Chad A.Mirkin: Array-Based electrical detection of DNA with Nanoparticle Probes. Science 2002 Feb. 22;295:1503-1506
  30. G.Chaplin, Nathan R. Franklin, Chong Zhou, Michael G.Chapline, Shu Peng, Kyeongjue Cho, Hongjue Dai: Nanotube molecular wires as chemical sensors. Science 2000 Jan.28; 287:622-625
  31. Yun Wei, Charles Cao, Rongchao Jin, Chad A.Mirkin: Nanoparticles with Raman spectroscopic Fingerprints for DNA and RNA detection. Science 2002 Aug.30; 297:1536-1540

The above article was presented as a poster at the 38th Annual Scientific Congress of the Head and Neck Surgeons of South Africa, Presidential Protea Hotel, Cape Town, South Africa, in October, 2002.             

Read Other Scientific PRESENTATIONS:

1. OLUSESI, A.D. Between The Cuticular Plate And The Synaptic Junction –Nanootological Re-Examination Of The Auditory Mechanism’s Missing Link

2. OLUSESI, A.D. Hearing Forever! – Nanootological Treatment Option For Presbycusis

3. OLUSESI, A.D. Sensorineural Hearing Loss - The Journey So Far

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